Immune Response Evaluation Criteria In Solid Tumors Research Articles

Real-life multi-center retrospective analysis on nivolumab in difficult-to-treat patients with advanced hepatocellular carcinoma.

BACKGROUNDHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The landscape of the systemic treatment for advanced HCC is changing quickly, and recently, the standard of care became either atezolizumab plus bevacizumab or tremelimumab plus durvalumab in the single tremelimumab regular interval durvalumab regimen. Nivolumab monotherapy has proven to be effective sometimes for advanced HCC and could be a valuable treatment option for patients outside current treatment indications and reimbursement criteria for the standard of care. This is a particular population of interest.AIMTo evaluate the real-world effectiveness of nivolumab monotherapy in patients with advanced HCC who are not eligible for other treatment.METHODSWe conducted a retrospective, multicentric study including 29 patients with advanced HCC from 3 Belgian tertiary hospitals. All patients had had prior chemotherapy or were intolerant or ineligible for treatments. All study subjects received nivolumab 3 mg/kg in monotherapy, administered once every two weeks intravenously. Treatment continued until disease progression, severe adverse events or death. Data were retrieved from patients’ medical records. The outcome parameters such as radiological response according to response evaluation criteria in solid tumors (RECIST) criteria, the biological response through the evolution of the alpha-fetoprotein (AFP) level, and clinical response considering both the Child–Pugh (CP) score and the World Health Organization (WHO) performance status (PS) were reported. A safety profile was also reported. Statistical analysis was performed using the SPSS Statistics 27 statistical software package.RESULTSThe radiological overall response rate (defined as complete or partial response according to the immune RECIST and modified RECIST criteria) to nivolumab monotherapy was 24.1%. The biological overall response rate (defined as a decrease of ≥ 25% in AFP blood level) was 20.7%. Radiological and biological responses were significantly associated both with each other (P < 0.001) and with overall survival (P < 0.005 for radiological response and P < 0.001 for biological response). Overall survival was 14.5 mo (+/- 2.1), and progression-free survival was 10.9 mo (+/- 2.3). After 4 mo of treatment, 78.3% of patients remained clinically stable or even showed improvement in WHO PS. Grade 3 adverse events occurred in 17.2% of patients, none had grade 4 adverse events, and no patients ceased nivolumab due to adverse events.CONCLUSIONNivolumab monotherapy is a good treatment choice in frail patients with HCC who are ineligible for the standard of care or other validated systemic treatments.

Recommended phase 2 dose (RP2D) of HB-200 arenavirus-based cancer immunotherapies in patients with HPV16+ cancers.

2517 Background: Treatment options are limited for patients with recurrent or metastatic human papillomavirus 16 positive (HPV16+) cancers. Generation and maintenance of HPV16+ cancers requires stable expression of HPV16-specific E7 and E6 oncoproteins, which are also a source of tumor-specific immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein and infect antigen presenting cells to induce tumor-specific T cell responses. The Phase 1 part of this study of HB-200 therapy (HB-201 single-vector therapy and HB-202/HB-201 two-vector alternating therapy) was conducted to determine RP2D for further exploration alone or in combination with pembrolizumab. Methods: The Phase 1 part used a 3+3 dose escalation design with up to 3 dose levels (DLs) of HB-201 and 4 DLs of HB-202/HB-201 explored. Patients with HPV16+ head and neck squamous cell carcinoma (HNSCC) or with other HPV16+ cancers were evaluated. Safety, tolerability, immunogenicity, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST were assessed to determine RP2D. Results: As of January 2022, 65 patients with a median of 3 prior anticancer treatments have been enrolled in the Phase 1 part of the study. All had HPV16+ confirmed genotype; the most common primary site was oropharynx, followed by anal and cervix. Adverse events were generally mild or moderate. For HB-201, 3 DLs, 2 dosing schedules and 2 administration routes were assessed across 40 patients. At DL3 of HB-201 administered intravenously (IV), dose-limiting toxicity (DLT) occurred in 1/6 patients in the HNSCC group (Grade 4 encephalopathy, fully recovered) and 1/2 patients in the non-HNSCC group (Grade 3 rash, fully recovered). Preliminary safety, efficacy, and immunogenicity data support IV injection of DL3 (5 × 107 units) every 3 weeks (Q3W) as the RP2D for HB-201 single-vector therapy. For HB-202/HB-201, 4 DLs and 2 administration routes were assessed across 25 patients. At DL4 of HB-202/HB-201 IV, 1/5 subjects in the HNSCC group reported a DLT (Grade 4 hepatitis, recovering at time of discontinuation). RP2D for HB-202/HB-201 will be determined in the very near future. Tumor control, including partial response, have been observed in subjects treated with either HB-201 or HB-202/HB-201 as monotherapy. Conclusions: HB-201 and HB-202/HB-201 were generally well tolerated and showed preliminary antitumor activity in heavily pre-treated patients with HPV16+ solid tumors. DL3 was selected as RP2D for HB-201 monotherapy. In the Phase 2 part of the study a combination of HB-201 at 5 × 106 units IV Q3W with pembrolizumab is being tested in HPV16+ HNSCC patients. Clinical trial information: NCT04180215.

Immune-related dissociated response as a specific atypical response pattern in solid tumors with immune checkpoint blockade.

Immune checkpoint blockade using immune checkpoint inhibitors, including cytotoxic T-lymphocyte-associated antigen–4 and programmed cell death protein-1/programmed cell death ligand–1 inhibitors, has revolutionized systematic treatment for advanced solid tumors, with unprecedented survival benefit and tolerable toxicity. Nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab are currently approved standard treatment options for various human cancer types. The response rate to immune checkpoint inhibitors, however, is unsatisfactory, and unexpectedly, atypical radiological responses, including delayed responses, pseudoprogression, hyperprogression, and dissociated responses (DRs), are observed in a small subgroup of patients. The benefit of immunotherapy for advanced patients who exhibit atypical responses is underestimated according to the conventional response evaluation criteria in solid tumors (RECIST). In particular, DR is considered a mixed radiological or heterogeneous response pattern when responding and nonresponding lesions or new lesions coexist simultaneously. The rate of DR reported in different studies encompass a wide range of 3.3–47.8% based on diverse definition of DR. Although DR is also associated with treatment efficacy and a favorable prognosis, it is different from pseudoprogression, which has concordant progressive lesions and can be regularly captured by immune RECIST. This review article aims to comprehensively determine the frequency, definition, radiological evaluation, probable molecular mechanisms, prognosis, and clinical management of immune-related DR and help clinicians and radiologists objectively and correctly interpret this specific atypical response and better understand and manage cancer patients with immunotherapy and guarantee their best clinical benefit.

Phase 1 first-in-human study of ABBV-184 monotherapy in adult patients with previously treated acute myeloid leukemia or non-small cell lung cancer.

TPS2674 Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive therapeutic target in cancer, due to its broad expression in solid tumors and hematologic malignancies but limited expression in normal tissues. Elevated survivin expression is associated with an increased invasive phenotype and worse clinical outcomes. ABBV-184 is a first-in-class T-cell receptor (TCR)/anti-cluster of differentiation 3 (CD3) bispecific molecule. It is composed of a soluble TCR that binds to a survivin-derived peptide bound to the class I MHC allele HLA-A2:01 expressed on tumor cells and to the CD3 receptor on T cells. Preclinical data have demonstrated that treatment with ABBV-184 results in T-cell activation, proliferation, and redirected cytotoxicity of HLA-A2:01–positive target cell lines. This first-in-human trial evaluates ABBV-184 monotherapy in patients with previously treated acute myeloid leukemia (AML) or non-small cell lung cancer (NSCLC). Methods: Patients (≥18 years, Eastern Cooperative Oncology Group performance status ≤2, HLA-A2:01 restricted genotype) with relapsed or refractory AML or NSCLC are currently enrolling in this phase 1 multicenter, open-label trial (NCT04272203), which includes parallel dose-escalation and dose-expansion phases for both diseases. Primary objectives are to determine the recommended phase 2 dose (RP2D) of ABBV-184 (dose escalation) and to assess its preliminary efficacy (dose expansion). Secondary objectives include safety, tolerability, pharmacokinetics (PK), and immunogenicity assessments (dose escalation and dose expansion) and duration of response (dose expansion). Patients will receive intravenous infusion of ABBV-184 once weekly. Dose escalation of ABBV-184 is guided by a Bayesian optimal interval design and the RP2D will be determined on the basis of clinical safety, PK, and pharmacodynamic data. For patients with AML, disease assessment is performed according to modified European LeukemiaNet-International Working Group criteria. For patients with NSCLC, response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Treatment can continue until disease progression or intolerable toxicity. Biomarker assessments will include longitudinal profiling of peripheral blood immune cells and cytokines, analysis of HLA-A2 and survivin levels on AML bone marrow blasts and NSCLC tumor biopsies, and retrospective correlations of biomarker data with antitumor activity. Enrollment initiated in Sep 2020, with 7 patients enrolled as of Jan 2021. Clinical trial information: NCT04272203.

First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers.

2502 Background: Human papillomavirus 16 (HPV16) is linked to several cancer types. Treatment options are limited for patients with HPV16 positive (HPV16+) recurrent or metastatic cancers. Generation and maintenance of HPV16+ malignant state require stable expression of HPV16-specific E7 and E6 oncoproteins, also a source of immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein to induce tumor-specific T-cell responses. This is a first-in-human phase 1/2 study of HB-201 monotherapy and HB-201 &amp; HB-202 alternating 2-vector therapy. Dose escalation is ongoing with a 3+3 design. Methods: Phase 1 is assessing different regimens and dose levels of HB-201 monotherapy and HB-201 &amp; HB-202 alternating 2-vector therapy given intravenously (IV) with or without an initial intratumoral administration. The patient population includes HPV16+ head and neck squamous cell carcinoma (HNSCC) and other HPV16+ cancers. Safety, tolerability, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST are assessed. Results: As of Jan 2021, 25 patients with a median of 3 prior anticancer treatments have been enrolled. All had HPV16+ confirmed genotype; the most common primary site was oropharynx (72%). No dose-limiting toxicities were reported. Treatment-emergent adverse events (TEAEs) occurred in 21 patients (84%), were generally mild or moderate, with events related to study drug reported in 14 patients (56%). TEAEs reported in &gt;10% of patients regardless of causality included fatigue, pyrexia, nausea, decreased appetite, anemia, arthralgia, chills, constipation, diarrhea, hypertension, influenza-like illness, pneumonia, and vomiting. Serious TEAEs developed in 6 patients (24%), including 1 with grade 5 hemorrhagic shock deemed unrelated to study drug. Grade 3 fatigue was the only serious or grade ≥3 TEAE assessed as related to study drug. TEAEs caused no treatment discontinuation. There were 18 patients evaluable for efficacy. For the 16 patients on HB-201 monotherapy, assessment of target lesions showed 2 partial responses (including 1 patient with an unconfirmed immune CR) and 6 patients had stable disease (SD). For the 2 patients on HB-201 &amp; HB-202 alternating therapy, both had SD. So far, the longest duration of response was 4.8 months (144 days) and the maximum decrease in tumor diameter was 60%, both seen in HNSCC patients receiving HB-201 IV. Conclusions: HB-201 monotherapy and HB-201 &amp; HB-202 2-vector alternating therapy were generally well-tolerated and showed preliminary antitumor activity as monotherapy in heavily pre-treated patients with HPV16+ HNSCC and other solid tumors. Clinical trial information: NCT04180215.

C-reactive protein at 1month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma.

Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. The median follow-up was 8.3months (range 0.2-29.8months). The median PFS period was 4.5months and the median immune-PFS (iPFS) period was 5.3months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (≥ 2) at start of treatment and CRP level at 1month after treatment (≥ 1.5mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (≥ 1.5mg/dL) obtained good iPFS if CRP was decreased (< 1.5mg/dL) 1month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. Our results indicated that the CRP level at 1month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.

Objective response rate assessment in oncology: Current situation and future expectations.

The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials. World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) are anatomic response criteria developed mainly for cytotoxic chemotherapy. These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography (CT) or magnetic resonance imaging. Anatomic response criteria may not be optimal for biologic agents, some disease sites, and some regional therapies. Consequently, modifications of RECIST, Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors. Despite its limitations, RECIST v1.1 is validated in prospective studies, is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents. Finally, some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors. Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging. Some graphical methods may be useful to show longitudinal change in the tumor burden over time. Tumor tissue is a tridimensional heterogenous mass, and tumor shrinkage is not always symmetrical; thus, metabolic response assessments using positron emission tomography (PET) or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments. The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage, possibly preventing delays in drug approval. Computer-assisted automated volumetric assessments, quantitative multimodality imaging in radiology, new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.

Preliminary Phase 1 Results of the PD-1 Inhibitor ABBV-181 in Japanese vs Western Patients With Advanced Solid Tumors

Abstract Background ABBV-181 is a monoclonal antibody that binds to cell surface programmed cell death 1 (PD-1). Dose-finding data have been previously reported (Powderly et al, Ann Oncol 2018). This report summarizes ABBV-181 monotherapy data from Japanese (JPN) and cohort-matched Western (WST) patients (pts) enrolled in the first-in-human study evaluating ABBV-181 in pts with previously treated advanced solid tumors (NCT03000257). Methods Pts received ABBV-181 in a 3 + 3 dose-escalation design at 1, 3, and 10 mg/kg IV every 2 weeks (Q2W) until progression (JPN pts: 3 and 10 mg/kg only) and a basket expansion cohort at a recommended phase 2 dose (RP2D). Response was assessed Q8W per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Serial pharmacokinetic (PK) and pharmacodynamic samples were collected. Results As of Nov 2018, 56 pts (JPN: 11) were enrolled (total and JPN pts, median days on treatment [range], 1 mg/kg: 12, 120 [43-653]; 3 mg/kg: 10 and 4, 64 [1-134] and 29 [15-106]; 10 mg/kg: 11 and 4, 64 [1-225] and 29 [1-85]; basket: 23 and 3, 29 [1-353] and 15 [15-16]). Adverse events (AEs) were reported in (total, JPN pts): 10, 4 (3 mg/kg); 10, 3 (10 mg/kg); and 22, 2 (basket), with 5, 1 (3 mg/kg); 4, 0 (10 mg/kg); and 15, 1 (basket) pts having Grade (G)≥3 AEs. No dose-limiting toxicities or drug-related G5 AEs were reported. The most common G ≥ 1 AEs in JPN pts were (%): pyrexia (36), anemia (27), constipation (18); G ≥ 3 AEs were: anemia, decreased appetite, progression (9% each, all unrelated to ABBV-181). One G5 AE of progression was reported. Seven of 11 JPN pts discontinued ABBV-181 (all for disease progression). ABBV-181 PK appears dose-proportional and comparable in JPN and WST pts. ABBV-181 led to complete PD-1 receptor occupancy, similar kinetics of cytokine induction, and transient T-cell changes in JPN and WST pts. Conclusion These results support a RP2D of 250 mg Q2W, 375 mg Q3W, or 500 mg Q4W in both JPN and WST pts.

1748P - Phase I open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of ABBV-181 and rovalpituzumab tesirine (ROVA-T) in patients with small cell lung cancer

1748P - Phase I open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of ABBV-181 and rovalpituzumab tesirine (ROVA-T) in patients with small cell lung cancer

Tumor Response Criteria in Oncoimaging: RECIST Criteria and beyond—Part 2

AbstractThe rapid recent advances in oncology have made the dream of precision oncology a reality, with targeted therapy available for various tumors depending on the molecular genotype. This has led to the corresponding development of personalized radiology as well, with various tumor response criteria used to characterize disease response/progression depending on chemotherapy used. In these two review articles, we review the various tumor response criteria widely applied in both research and clinical settings. These include the classic size-based criteria such as RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 and the WHO (World Health Organization) criteria, as also various other criteria such as Choi and modified Choi criteria for tumors treated by targeted therapy, EASL (European Association for the Study of the Liver) and modified RECIST (mRECIST) criteria for hepatocellular carcinomas, immune-related response criteria (irRC) and immune RECIST (iRECIST) for patients on immunotherapy. Other clinically important criteria such as PERCIST (PET Response Criteria In Solid Tumors) for positron emission tomography–computed tomography (PET-CT), and the MD Anderson criteria for evaluating bone metastases are also highlighted.

Tumor Response Criteria in Oncoimaging: RECIST Criteria and beyond—Part 1

AbstractThe rapid recent advances in oncology have made the dream of precision oncology a reality, with targeted therapy available for various tumors depending on the molecular genotype. This has led to the corresponding development of personalized radiology as well, with various tumor response criteria used to characterize disease response/progression depending on chemotherapy used. In these two review articles, we review the various tumor response criteria widely applied in both research and clinical settings. These include the classic size-based criteria such as RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and the WHO (World Health Organization) criteria, as also various other criteria such as Choi and modified Choi criteria for tumors treated by targeted therapy, EASL and modified RECIST (mRECIST) criteria for hepatocellular carcinomas, and immune-related response criteria (irRC) and immune RECIST (iRECIST) for patients on immunotherapy. Other clinically important criteria such as PERCIST (PET Response Criteria In Solid Tumors) for positron emission tomography–computed tomography (PET-CT) and the MD Anderson criteria for evaluating bone metastases are also highlighted.

Radiologic Pseudoprogression during Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer

Anti-programmed cell death protein 1 (PD-1) therapy can lead to unconventional tumor responses, including radiologic pseudoprogression. Here we havedetermined the real-world incidence of radiologic pseudoprogression in advanced NSCLC and compared radiologic response criteria for assessment of disease response. The electronic medical records of all patients with NSCLC who were receiving anti-PD-1 therapy at our institution over a 3-year period were retrospectively reviewed, and patients with clinically suspected radiologic pseudoprogression were identified. Patients without available follow-up imaging or clinical data were excluded. Imaging examinations were then analyzed to determine whether progression was confirmed on subsequent reimaging. Assessments of tumor response by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST 1.1), the unidimensional immune-related response criteria (iRRC), and the iRECIST criteria for all patients were performed and compared. A total of 228 consecutive patients began receiving anti-PD-1 therapy over a 3-year period. Of the 166 of these patients who were evaluable, most (80%) received nivolumab. Fifteen patients (9%) were clinically suspected of having radiologic pseudoprogression on account of tumor enlargement and/or development of new lesions on computed tomography images during the first 4 to 6 weeks of therapy, and they continued receiving anti-PD-1 therapy. Three of these patients (2%) demonstrated evidence of radiologic pseudoprogression at first reimaging. The iRRC and immune RECIST criteria were more accurate in classifying radiologic pseudoprogression as nonprogression; none of the three cases were deemed progression by the iRRC or immune RECIST, whereas all three cases were determined to be progression according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Radiologic pseudoprogression is a clinical challenge but an uncommon occurrence in patients with NSCLC who are receiving anti-PD-1 therapy.

Immunotherapy and the role of imaging.

Significant advances in the genetic and molecular characterization of cancer have led to the development of effective immunotherapies. These therapeutics help the host immune system recognize cancer as foreign, promote the immune system, and relieve the inhibition that allows growth and spread of tumors. Experience with various immunotherapies, particularly the immunomodulatory monoclonal antibody ipilimumab, has demonstrated that unique patterns of response may be encountered that cannot be adequately captured by traditional response criteria, such as the World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), which have been used primarily with cytotoxic chemotherapies. In response to these observations, several novel response criteria have been developed to evaluate patients who receive immunotherapy, including immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST). These criteria are typically used in conjunction with RECIST version 1.1 in the clinical trial setting, because approval of new therapeutics by the US Food and Drug Administration relies on the responses derived from RECIST version 1.1. Finally, a wide variety of immune-related adverse events may affect patients who receive immunotherapy, many of which can be identified on imaging studies such as computed tomography, magnetic resonance imaging, and 2-deoxy-2-(fluorine-18)fluoro-D-glucose-positron emission tomography/computed tomography. In this review, the authors present the role of imaging in the evaluation of patients treated with immunotherapy, including the background and application of irRC, irRECIST, and iRECIST; the imaging of immune-related adverse events; and future directions in advanced imaging of immunotherapy. Cancer 2018;124:2906-22. © 2018 American Cancer Society.

Pitfalls in the radiological responseassessment of immunotherapy.

SummaryImmunotherapies comprise of a class of cancer therapies that are increasingly used for treatment of several cancer entities. Active immunotherapies encompassing immune checkpoint inhibitors are the most widespread class of immunotherapies, with indications for melanoma, non-small lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, and Hodgkin’s lymphoma. Immune checkpoint inhibitors have demonstrated unique response patterns that are not adequately captured by traditional response criteria such das the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization criteria. Consequently, adaptions of these criteria have been released such as the immune-related RECIST and immune RECIST, which account for the specialities of immunotherapies. Immunotherapies can cause a distinct set of adverse events such as pneumonitis, colitis, and hypophysitis. In addition, atypical treatment response patterns termed pseudoprogression have been observed. Thereby, new or enlarging lesions appear after treatment start and mimic tumor progression, which is followed by an eventual decrease in total tumor burden. In this review article we will describe pitfalls in the radiological response assessment of immunotherapies, focusing on pseudoprogression and imaging appearances of common immune-related adverse events.

Immunotherapy in Lung Cancer and the Role of Imaging

Lung cancer is the leading cause of cancer-related mortality and accounts for more deaths than breast, prostate, and colon cancers combined. Traditionally, treatment options have included surgery, chemotherapy, and radiation therapy. Continual advances in the characterization of lung cancer have resulted in the development of effective immunotherapies. These agents help the immune system recognize tumors as foreign, stimulate the immune system, and relieve the inhibition that allows the growth and spread of cancer. Conventional response criteria such as the World Health Organization criteria and Response Evaluation Criteria in Solid Tumors (RECIST) have been used extensively in clinical trials; however, these guidelines have been optimized for use with traditional cytotoxic chemotherapy. Data from clinical trials employing immunotherapy has shown that unique responses may be seen with these agents that are not fully captured by conventional response criteria. In response to these observations, several modified criteria have been developed for use with immunotherapy, including immune-related response criteria, immune-related RECIST, and immune RECIST. As the use of immunotherapy continues to grow, there is increasing recognition of immune-related adverse events, which may manifest on imaging examinations.

Immunotherapy in Non-Small Cell Lung Cancer Treatment: Current Status and the Role of Imaging.

Lung cancer remains the leading cause of cancer-related mortality and is responsible for more deaths than breast, prostate, and colon cancer combined. Most patients are diagnosed with advanced disease at the time of presentation, and treatment options have traditionally included surgery, chemotherapy, and/or radiation. However, significant advances in the molecular characterization of lung cancer have led to the creation of effective immunotherapies that assist in the recognition of cancer as foreign by the host immune system, stimulate the immune system, and relieve the inhibition that allows tumor growth and spread. Extensive experience with the immunomodulatory monoclonal antibody ipilimumab has demonstrated that unique responses may be seen with immunotherapies that are not adequately captured by traditional response criteria such as the World Health Organization criteria and Response Evaluation Criteria in Solid Tumors (RECIST). Consequently, several modified criteria have been developed to evaluate patients treated with immunotherapy, including immune-related response criteria, immune-related RECIST, and immune RECIST. Finally, patients undergoing immunotherapy may develop a wide variety of immune-related adverse events with which the radiologist must be familiar. In this article, we present the fundamental concepts behind immunotherapy, specific agents currently approved for the treatment of lung cancer, and immune-related adverse events. The role of imaging in the evaluation of these patients will also be discussed, including the general principles of treatment response evaluation, specific response criteria adopted with these agents, including immune-related response criteria, immune-related RECIST, and immune RECIST, and the imaging of immune-related adverse events.

RECIST 1.1 versus immune-related RECIST and immune-related response criteria in assessing response to nivolumab in patients with lung, renal, and head and neck cancers.

e14609 Background: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is reported to underestimate response to immunotherapeutic drugs. Therefore, immune related RECIST (iRECIST) based on RECIST 1.1 and immune related response criteria (IRRC) based on WHO response criteria have been studied, mainly in patients with melanoma. Whether RECIST 1.1 underestimates responses in other cancers is not well known. Aim of the present study is to assess response rates to PDL-1 inhibitor Nivolumab in lung, renal and head and neck (H&amp;N) cancers using RECIST 1.1, iRECIST and IRRC. Methods: We reviewed patients from 2012 to present with lung, renal, H&amp;N cancers treated with Nivolumab at John h Stroger Jr. Hospital of Cook County. Incomplete charts and those treated for less than 4 cycles of Nivolumab were excluded. Data was analyzed using descriptive statistics and Fisher exact test. Results: 47 charts were reviewed, 27 met the inclusion criteria. 17 lung (14 adeno, 3 squamous), 7 renal (5 clear cell) and 3 H&amp;N cancer patients were included. Average age was 58.2yrs, 20(74%) were male. Average treatment was for 13 cycles. Response was assessed after at least 4 cycles. Disease control rate for lung, renal, head and neck cancer was 70%,58%, 33% respectively with RECIST 1.1 criteria compared to 77%, 71% and 66% respectively using immune RECIST or IRRC (P &gt; 0.05). No patient developed pseudoprogression. Two had progressive disease per RECIST 1.1 but stable disease with iRECIST and IRRC. 26 of the 27 patients showed concordance between iRECIST and IRRC. One patient had stable disease per iRECIST but partial response per IRRC. Average survival after treatment initiation was 8.3 months for lung, 9.1 months for renal and 5.6 months for H&amp;N cancer. Treatment was discontinued in 2 patients based on progression per RECIST 1.1, both patients had stable disease per iRECIST&amp; IRRC. Conclusions: Trend towards underestimation of treatment response using RECIST 1.1 criteria compared to iRECIST or IRRC was observed. Strong concordance was observed between iRECIST and IRRC. Given relative ease of use, iRECIST might be favored over IRRC in response evaluation for immunotherapeutic drugs.